Prevalence and predisposing factors for fatigue in patients with chronic renal disease undergoing hemodialysis: a cross-sectional study

ABSTRACT BACKGROUND: Patients with chronic renal disease and undergoing hemodialysis are at a high risk for developing several complications. Fatigue is a common, troubling symptom that affects such patients and can contribute to unfavorable outcomes and high mortality. OBJECTIVE: This cross-sectional study aimed to evaluate the prevalence of fatigue in Brazilian patients with chronic kidney disease undergoing hemodialysis and determine the predisposing factors for fatigue. DESIGN AND SETTING: An observational, cross-sectional, descriptive study was conducted in two renal replacement therapy centers in the Greater ABC region of São Paulo. METHODS: This study included 95 patients undergoing dialysis who were consecutively treated at two Brazilian renal replacement therapy centers between September 2019 and February 2020. The Chalder questionnaire was used to evaluate fatigue. Clinical, sociodemographic, and laboratory data of the patients were recorded, and the Short Form 36 Health Survey, Pittsburgh Sleep Quality Index, and Beck Depression Inventory were administered. RESULTS: The prevalence of fatigue in patients undergoing hemodialysis was 51.6%. Fatigue was independently associated with lower quality of life in terms of physical and general health. Patients with fatigue had a higher incidence of depression (65.9% vs. 34.1%, P = 0.001) and worse sleep quality (59.1% vs. 49.9%; P = 0.027) than those without fatigue. CONCLUSION: Prevalence of fatigue is high in patients undergoing hemodialysis and is directly related to physical and general health.


OBJECTIVE
This cross-sectional study aimed to assess the prevalence of fatigue in patients with chronic kidney disease undergoing renal replacement therapy in the form of hemodialysis at two dialysis centers in the ABC Paulista region. This study also examined the predisposing factors for fatigue in the study population.

METHODS
This observational, cross-sectional, descriptive study analyzed the prevalence of and predisposing factors for fatigue in patients with chronic kidney disease undergoing hemodialysis. The study was conducted at two renal replacement therapy centers in the Greater ABC region of São Paulo. One of the centers was located at a high-complexity hospital treating patients from the Unified Health System; the other was located in a center treating patients from the private sector.
Patients with stage 5 chronic kidney disease who were undergoing hemodialysis were eligible to participate in the study. The exclusion criteria were as follows: peritoneal dialysis, age < 21 years, dialysis for < 12 months, psychiatric disorders with cognitive deterioration, active infectious or autoimmune disease, liver failure, and metastatic malignant neoplasms.
The study protocol was approved by our institution's ethics committees for research on humans under the CAAE number 24471419.7.0000.0082 (Decision number: 3.705.408) on November 14, 2019. The study was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consents before any study-related procedures were performed.
The patients' demographic characteristics (age, sex, race, marital status, education, and income) were collected directly from clinical databases and records. Clinical data, including the cause of chronic kidney disease, existing comorbidities, medications being used, treatment complications, and duration of dialysis, were collected from the patients' medical records. The patients' laboratory parameters, including the serum hemoglobin, albumin, urea, parathyroid hormone, ferritin, calcium , phosphorus, and potassium levels and dialysis adequacy were also collected from the system. The Chalder Fatigue Scale is a self-administered questionnaire used to measure the extent and severity of fatigue in both clinical and non-clinical epidemiological populations. This scale consists of 11 items which are answered on a 4-point scale ranging from asymptomatic to maximum symptomology ("better than usual, " "no worse than usual, " "worse than usual, " and "much worse than usual"). The total score ranges from 0 to 33 and spans two dimensions: physical and psychological fatigue. 9 The SF-36 questionnaire consists of the following eight multiitem scales: physical functioning, body pain, mental health, general   health, vitality, role limitation due to emotional problems, role limitations due to physical health, and social

Statistical analysis
Qualitative variables are described using absolute and relative frequencies, whereas, quantitative variables are presented as summary measures (mean, standard deviation, median, minimum, and maximum). 13 The prevalence of fatigue was analyzed according to each qualitative characteristic, using absolute and relative frequencies. Chi-square or likelihood ratio tests were used to evaluate the association between the characteristics and presence of fatigue. Quantitative characteristics were described in terms of their association with fatigue and compared using Student's tor Mann-Whitney U-tests. 13 Odds ratios (OR) were calculated with unadjusted 95% confidence intervals (CI). A binary logistic regression model was used to identify the presence or absence of fatigue for each of the evaluated characteristics. The model included descriptive sex and age characteristics with a P value < 0.20 and the probability for fatigue.
A backward stepwise regression selection method was used, with the input and output criteria of the final model at 5%. 14 All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) for Windows (version 20.0; IBM, Armonk, New York, United States). Clinical significance was set at P < 0.05.

RESULTS
A total of 155 patients were registered at two hemodialysis clinics in the Greater ABC region of São Paulo. Of these, 60 patients were excluded for the following reasons: cognitive deterioration (4), diagnosis of liver failure (1), withdrawal of consent (5), refusal to participate (7), dialysis for <12 months (30), hospitalization (6), diagnosis of an active infection (3), and diagnosis of cancer (4). The remaining eligible 95 patients, who were diagnosed with chronic kidney disease and were undergoing hemodialysis were included in the study (Figure 1) The laboratory examination results of the patients' samples were predominantly within the normal range expected for the population studied. 15 There were no significant differences in the laboratory values between patients with or without fatigue.
All the patients in our study had a low quality of life, depressive symptoms (34.7%), and a high prevalence of sleep disorders (69.5%). Among the 95 enrolled patients undergoing hemodialysis, the prevalence of fatigue was 51.6% ( Table 2). Although depression was more frequently seen in women in our study, there was no significant difference in the incidence of depression in either sex (P = 0.392) (data not shown).  Exclude those that refused to participate (n = 07) Binary analysis revealed that fatigue was not significantly associated with demographic or clinical characteristics when analyzed in isolation (P > 0.05) ( Table 3). However, quality of life domains were significantly lower in patients with fatigue than in those without fatigue (P < 0.05). Additionally, the prevalence of depression (P = 0.001) and poor sleep quality (P = 0.027) were significantly higher among patients with fatigue than in those without fatigue ( Table 4). In

DISCUSSION
Fatigue has a high prevalence among patients with chronic kidney disease worldwide, with several unfavorable outcomes.
Fatigue is considered to be an independent risk factor for increased mortality in such patients. 16 Although studies on this subject are scarce in Brazil, our findings suggest that the observed high prevalence of fatigue is comparable to the current scientific evidence. 17,18 There was no statistical difference in the presence of fatigue between the sexes; this result is in contrast to previous studies that suggest that fatigue is more prevalent in females. 19 Demographic characteristics can be predictors of fatigue; 20  Fatigue may be related to objective laboratory data. Univariate analysis has shown that fatigue is associated with changes in the serum parathyroid hormone, iron, urea, calcium, albumin, and hemoglobin levels; a multivariate analysis detected a relationship between fatigue and serum parathyroid hormone. 7 Resistance to erythropoietin, independent of the degree of anemia and level of transferrin saturation, is associated with factors related to fatigue. 23 Clinical indicators are objective and reflect a combination of several symptoms; one symptom alone cannot significantly influence serum and biochemical indicators. 7 In addition, patients undergoing hemodialysis are monitored by nephrologists who encounter frequent clinical changes, which may influence the correlation with symptoms. In this study, there was no statistically significant difference in the laboratory results between the patients with and without fatigue, which may have been due to the immediate treatment of the biochemical changes. The fact that patients with chronic kidney disease have varying symptoms may reflect a multidimensional issue, which has been suggested in previous clinical studies. 24 Up to 50% of patients undergoing hemodialysis have some degree of depression that impacts the quality of life, decreases the adherence to treatment, and increases the rate of suicide and mortality. 25 Tryptophan metabolites, the precursors of serotonin and melatonin, are increased in patients undergoing dialysis and may be associated with depression and fatigue. 26 Considering that there is a causal relationship between fatigue and depression, the finding of increased fatigue in patients undergoing dialysis suggests the need for further investigation and potential diagnosis of depression. Various types of fatigue, such as physical, mental, and emotional, have been described as precursors of depression; furthermore, fatigue has been reported in 22-49% of patients treated with antidepressants and in depression remission. 27 However, bivariate analyses indicate that depression is causally correlated with an impact on all fatigue types. 28 Depression was found to be more prevalent in patients with fatigue in our study. Sleep alterations affect 40-83% of patients undergoing dialysis, [29][30][31] and their association with restless leg syndrome increases the risk of death 30 . The treatment of restless leg syndrome reportedly leads to an improvement in fatigue-related symptoms. 30 Patients with chronic kidney disease undergoing hemodialysis have increased tryptophan catabolism, an essential amino acid that increases serotonin production in the central nervous system. A subsequent decrease in the serum concentration of tryptophan could be related to changes in the sleep quality and fatigue. 6,26 A study demonstrated that non-pharmacological treatments that decreased anxiety were associated with a reduction in fatigue and improvement in sleep quality. 31 Additionally, a meta-analysis showed that performing aerobic exercises during dialysis sessions and acupuncture sessions can improve the sleep quality and decrease the reliance on drugs for the treatment of sleep disorders; 32 performing aerobic exercises before the dialysis session could also have similar benefits. 33 Our study established a significant association between sleep disorders and fatigue, suggesting that the treatment of these disorders could decrease the prevalence of fatigue and improve the quality of life.
The quality of life in patients undergoing hemodialysis influences their prognosis and mortality rate. Thus, diagnosing sleep disorders and fatigue is as an integral part of the treatment. 34,4 Our results were comparable to that of a study where the quality of life was inversely related to fatigue and depression. Additionally, married patients whose treatments were financially supported experienced a better quality of life. 34 Our study confirmed this inverse relationship, especially in the domains of physical and general health. Physical exercise programs performed during the intradialytic period reportedly have a positive impact on the patient's quality of life, depression, and fatigue. 35 Our study had several limitations. Due to the observational nature of this study, we could not infer a cause-and-effect relationship among the observed variables, that is, between the occurrence of fatigue and depression or sleep disorders. Therefore, caution should be exercised when applying these results to patients undergoing hemodialysis in daily practice. Further prospective studies are needed to determine the etiology of fatigue and assess its prognostic role in patients with chronic kidney disease undergoing hemodialysis.

CONCLUSION
Fatigue is common among patients undergoing hemodialysis and is associated with depression and sleep disturbances.
Clinicians should proactively investigate signs of fatigue to avoid its impact on the quality of life in patients with end-stage kidney disease.